Steroid epoxides are an important class of oxysterols (oxygenated derivatives of cholesterol) involved in the regulation of cell proliferation and cholesterol homeostasis. They are versatile intermediates for steroid synthesis and useful probes for biochemical studies of enzymes. Steroid epoxides are also useful intermediates for the preparation of other oxysterols. For example, α- and β-epoxides of cholesterol are auto-oxidation products of cholesterol in vivo, and both are cytotoxic and mutagenic. The isomeric α- and β-epoxides are hydrolysed by cholesterol 5,6-epoxide hydrolase to cholestane-3β,5α,6β-triol which has potent hypocholesterolemic activity. On the other hand, both epoxides inhibit the cholesterol 7α-hydroxylase which catalyzes the rate-determining step of bile acid synthesis. As 5α,6α-epoxides are readily available via epoxidation of Δ5-unsaturated steroids with peracids, there have been extensive studies on the biological actions of those epoxides and their derivatives. In contrast, much less is known about the 5β,6β-epoxides and their derivatives because they are difficult to obtain in high selectivity. More importantly, the 5β,6β-epoxy functionality is found in a number of naturally occurring steroids of antitumor activities, e.g., jaborosalactone A, withaferin A, and withanolide D.
Common organic oxidants such as 3-chloroperoxybenzoic acid (mCPBA) generally give α-epoxides as the major products for epoxidation of 3β-substituted Δ5-steroids and show poor selectivities for epoxidation of 3α-substituted Δ5-steroids except epi-cholesterol. This is because peracid epoxidation follows a concerted pathway via spiro transition states (α-TS and β-TS (TS=transition state); see FIG. 1). The β-TS suffers from steric interactions between the peracid and the C(10) angular methyl group for epoxidation of 3β-substituted Δ5-steroids, while both the β-TS and the α-TS encounter similar steric hindrance for epoxidation of 3α-substituted Δ5-steroids. Dioxiranes are new-generation reagents for oxidation under mild and neutral conditions. Unfortunately, poor selectivities were reported in epoxidation of 3β-substituted Δ5-steroids by either isolated or in situ generated dioxiranes. While dioxiranes also epoxidize olefins through a spiro TS, their steric environment is different from that of peracids. To minimize steric interactions, dioxiranes prefer to approach the C(5)═C(6) double bond of Δ5-steroids from the less-substituted side, i.e., away from the C(10)-angular methyl group and the C-ring of steroids (FIG. 1). Therefore, it is the potential steric interactions between the α-substituents of dioxiranes and the 3α and 4β substituents of steroids that determine the facial selectivity of epoxidation.
Yang et al., in U.S. Pat. No. 5,763,623 and in J. Org. Chem., 1998, vol. 63 pages 8952-8956, disclose the epoxidation of unfunctionalized olefins using various ketones. These references do not teach or suggest the epoxidation of Δ5-unsaturated steroids.
Cicala, G., et al., J. Org. Chem., 1982, vol. 47, pages 2670-2673, disclose the epoxidation of a Δ5-unsaturated steroid that is not a 3α-substituted Δ5-unsaturated steroid, and in which the ketone catalyst is acetone.
Marples, B. A., et al. Tetrahedron Lett., 1991, vol. 32, pages 533-536, disclose the epoxidation reactions of four Δ5-unsaturated steroids that are not 3ax-substituted Δ5-unsaturated steroids, and using a variety of ketones. In these reactions either no epoxide was observed, or the β/α-epoxide ratio was about 1:1.
Bovicelli, P., et al., J. Org. Chem., 1992, vol. 57, pages 2182-2184, disclose the epoxidation of a Δ5-unsaturated steroid that is not a 3α-substituted Δ5-unsaturated steroid, and using dimethyldioxirane. The β/α-epoxide ratio was about 3:1.
Boehlow, T. R., et al., Tetrahedron Lett., 1998, vol. 39, pages 1839-1842, disclose the epoxidation of a Δ5-unsaturated steroid that is not a 3α-substituted Δ5-unsaturated steroid, and using a variety of ketone catalysts.
Shi, Y., in PCT Publication No. WO 01/12616 A1, Feb. 22, 2001, discloses an epoxidation method combining an olefin substrate, a ketone catalyst, a nitrile compound, and hydrogen peroxide.
Shi, Y., in PCT Publication No. WO 98/15544, Apr. 16, 1998, discloses the use of a chiral ketal and an oxidizing agent with an olefin to generate an epoxide with high enantioselectricity.